Kruppel-like factor 15 regulates skeletal muscle lipid flux and exercise adaptation

Saptarsi M. Haldar, Darwin Jeyaraj, Priti Anand, Han Zhu, Yuan Lu, Domenick A. Prosdocimo, Betty Eapen, Daiji Kawanami, Mitsuharu Okutsu, Leticia Brotto, Hisashi Fujioka, Janos Kerner, Mariana G. Rosca, Owen P. McGuinness, Rod J. Snow, Aaron P. Russell, Anthony N. Gerber, Xiaodong Bai, Zhen Yan, Thomas M. NosekMarco Brotto, Charles L. Hoppel, Mukesh K. Jain

Research output: Contribution to journalArticlepeer-review

86 Scopus citations

Abstract

The ability of skeletal muscle to enhance lipid utilization during exercise is a form of metabolic plasticity essential for survival. Conversely, metabolic inflexibility in muscle can cause organ dysfunction and disease. Although the transcription factor Kruppel-like factor 15 (KLF15) is an important regulator of glucose and amino acid metabolism, its endogenous role in lipid homeostasis and muscle physiology is unknown. Here we demonstrate that KLF15 is essential for skeletal muscle lipid utilization and physiologic performance. KLF15 directly regulates a broad transcriptional program spanning all major segments of the lipid-flux pathway in muscle. Consequently, Klf15-deficient mice have abnormal lipid and energy flux, excessive reliance on carbohydrate fuels, exaggerated muscle fatigue, and impaired endurance exercise capacity. Elucidation of this heretofore unrecognized role for KLF15 now implicates this factor as a central component of the transcriptional circuitry that coordinates physiologic flux of all three basic cellular nutrients: glucose, amino acids, and lipids.

Original languageEnglish
Pages (from-to)6739-6744
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number17
DOIs
StatePublished - Apr 24 2012

Keywords

  • Fat
  • Mitochondria
  • Myocyte
  • Zinc finger

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